AIMS: To investigate the status of social isolation among middle-aged and elderly breast cancer patients and identify its influencing factors. Additionally, to explore the mediating role of self-perception of aging between frailty and social isolation, as well as the moderating effect of menopausal symptoms. DESIGN: A cross-sectional study guided by the Strengthening the Reporting of Observational Studies in Epidemiology. METHODS: This study was conducted on middle-aged and elderly breast cancer patients from September 2022 to February 2023 in Guangzhou, China. Related data were assessed by structural questionnaires. Correlation analysis and regression analysis were performed by SPSS 26.0 while PROCESS macro v4.0 was used to test the moderated mediation model. RESULTS: Breast cancer patients aged 45-82 years experienced moderate social isolation. It was influenced by educational level, residence, menopause symptoms, self-perception of aging, and frailty. The moderated mediation model involving self-perception of aging and menopausal symptoms for explaining how frailty causes social isolation was supported. The mediating role of self-perception of aging gradually strengthens as menopausal symptoms become severe. CONCLUSION: Social isolation resulting from frailty in middle-aged and elderly breast cancer patients is mediated by self-perception of aging, with menopausal symptoms amplifying this effect. Interventions focused on improving self-perception of aging and managing menopausal symptoms may help reduce social isolation by mitigating the impact of frailty. IMPACT: This study highlights the importance of addressing frailty, self-perception of aging, and menopausal symptoms in clinical nursing practice, which may help reduce social isolation among breast cancer patients. PATIENT OR PUBLIC CONTRIBUTION: Patients contributed by completing the questionnaire, ensuring the accuracy and completeness of the information with assistance from the research team.